The normal role of complement, which is part of the innate immune system, is in host defense. Complement defends against bacterial infection, links adaptive and innate immunity, and disposes immune complexes and the products of inflammatory injury.
The defensive functions are accomplished by biologically active products generated in the course of complement activation, which opsonise infectious agents, promote inflammation or lyse susceptible targets (Marzari et al., Eur J Immunol 32:2773-2782 (2002)). The complement system consists of about 25-30 plasma proteins which play a role in the immune system. The complement cascade is activated by at least three major pathways. The classical pathway is typically activated by immune-complexes, the alternative pathway can be activated by unprotected cell surfaces, and the mannose binding lectin (MBL) pathway is initiated by binding of MBL to cell surface carbohydrates (Trendelenburg, Swiss Med Wkly 137:413-417 (2007)).
All three pathways lead to the cleavage of C5 by the C5 convertase. The result of this cleavage is release of C5a fragment, a potent inflammatory molecule, and C5b which initiates the membrane attack complex (MAC). The complement products, once released, do not differentiate between foreign and self targets and, if not tightly regulated, often cause extensive damage of bystander cells and tissues in clinical conditions associated with unrestricted complement activation (Marzari et al., 2002).
C5 is expressed intracellularly as a single pro-C5 peptide of 1676 amino acids that consist of an 18 residue signal sequence and an Arg-rich linker sequence (RPRR) situated between the mature N-terminal β chain and the C-terminal α chain. The mature C5 has a molecular weight of about 190 kDa, and consists of two polypeptide chains (α, 115 kDa and β, 75 kDa) which are connected by disulfide bonds. The C5 convertase cleaves C5 between residues 74 and 75 of the alpha chain to release the 74 amino acid C5a peptide and the C5b fragment which is subsequently incorporated into the membrane-attack complex (MAC).
Macular degeneration is a medical condition predominantly found in the elderly in which the center of the inner lining of the eye, known as the macula area of the retina, suffers thinning, atrophy, and in some cases, bleeding. This can result in loss of central vision, which entails inability to see fine details, to read, or to recognize faces. Pathogenesis of new choroidal vessel formation is poorly understood, but factors such as inflammation, ischemia, and local production of angiogenic factors are thought to be important.
Despite current treatment options for treating diseases and disorders associated with the classical or alternative component pathways, particularly AMD, there remains a need for finding specific targets that lead to treatments which are effective and well-tolerated.